Summary of Teratology Studies:
MAJOR CONGENITAL ANOMALIES
Several cohort studies have found marginal evidence supporting an association of maternal use of acetaminophen during the first and second trimesters of pregnancy with congenital cryptorchidism. This includes 22,449 exposed male children in the Danish National Birth Cohort (hazard ratio=1.33, 95% confidence interval 1.00-1.77) (Jensen et al., 2010, 2011) and 3184 boys enrolled in a Dutch study (odds ratio=1.85, 95% confidence interval 1.02-3.37) (Snijder et al., 2012). A dose-dependent relationship was found between the occurrence of cryptorchidism and the frequency of maternal acetaminophen use during the first or second trimester of pregnancy in an independent study of 491 boys in Denmark and Finland (Kristensen et al., 2011).
The overall prevalence of congenital anomalies was no greater than expected among 26,424 children whose mothers used acetaminophen during the first trimester of pregnancy in the Danish National Birth Cohort (Rebordosa et al., 2008). However, an association was seen with congenital anomalies of the ear, face, or neck in this study (hazard ratio=1.82, 95% confidence interval 1.11-2.99). Congenital anomalies were observed 2.3 times more often than expected (95% confidence interval 1.0-5.4 times) in a Danish study of 55 infants whose mothers were given prescriptions for daily acetaminophen treatment during the first trimester of pregnancy or in the month before conception (Thulstrup et al., 1999). The distribution of congenital anomalies in this study did not indicate a causal link with acetaminophen.
No association with maternal acetaminophen use and congenital anomalies was found among the infants of 9989 mothers who used acetaminophen during the first trimester of pregnancy in multiple cohort studies (Jick et al., 1981; Aselton et al., 1985; Rosa et al., 1993).
The frequency of maternal use of acetaminophen during the first trimester or anytime during pregnancy was no greater than expected among children with congenital anomalies (11,610 cases), microcephaly (166 cases), cardiac (466 cases) and renal (192 cases) anomalies, neural tube defects (538 cases), and gastroschisis (286 cases) in multiple case-control studies (Zierler & Rothman, 1985; Shaw et al., 1998; Abe et al., 2003; Cleves et al., 2004; Feldkamp et al., 2010; Kerr et al., 2019; Weber et al., 2019).
However, marginal positive findings have been reported in some case-control studies. Maternal first-trimester acetaminophen use was more frequent than expected among infants with amniotic bands involving only the limbs (53 cases, odds ratio=2.1, 95% confidence interval 1.1-3.9) or involving the face or neural tube, with or without limb involvement (20 cases, odds ratio=3.4, 95% confidence interval 1.1-10.3) (Werler et al., 2003). An association with maternal use of acetaminophen during embryogenesis was observed among 601 infants with primary cleft palate (odds ratio=3.7, 95% confidence interval 1.1-12.0) but not among 1374 infants with isolated cleft lip with or without cleft palate in the Hungarian Case-Control Surveillance of Congenital Anomalies (Puho et al., 2007). Overall acetaminophen use during pregnancy has also been associated with a slightly increased risk of gastroschisis (216 cases, odds ratio=1.5, 95% confidence interval 1.1-2.2) (Werler et al., 2002).
The frequency of maternal use of acetaminophen during embryogenesis was greater than expected among infants with tetralogy of Fallot (59 cases, adjusted odds ratio=1.6, 95% confidence interval 1.1-2.3) (Marsh et al., 2014). This result may be due to chance because of the large number of phenotypic comparisons made.
ADVERSE PREGNANCY AND NEONATAL OUTCOMES
The use of acetaminophen during pregnancy was not associated with adverse perinatal outcomes, including preterm birth, low birth weight or low weight for gestational age in a meta-analysis of several large cohort and case-control studies (Castro et al., 2022). Furthermore, no increased risk of preterm birth or low birth weight among women with autoimmune disorders who used acetaminophen in pregnancy was reported in the MotherToBaby prospective cohort study (Killion et al., 2021). In other cohort and case-control studies, the prevalences of stillbirth, miscarriage, or amniotic bands were not increased among 80,652 women who used acetaminophen anytime during pregnancy (Pastore et al., 1999; Li et al., 2003; Rebordosa et al., 2009; Feldkamp et al., 2010; Smarr et al., 2019).
A 2019 observational study from the prospective German Embryotox cohort found that third trimester acetaminophen use was not associated with ductus arteriosus closure or fetal renal impairment in infants born to 604 women who used acetaminophen during the third trimester (Dathe et al., 2019). Although a case series analysis of 25 cases of fetal ductus arteriosus constriction or closure suggested that an association with maternal acetaminophen use during pregnancy was likely (Allegaert et al., 2019), the data were limited by inadequate descriptions of used analgesic medications and lacked detail in some cases on dose and timing of prenatal acetaminophen use.
Hepatoxicity and nephrotoxicity occur as complications of acetaminophen overdosage in adults. Similar effects have been observed among infants born to women who took large therapeutic or toxic doses of acetaminophen late in pregnancy (Aw et al., 1999; Wilkes et al., 2005). Fetal distress and fetal death have occurred in pregnant women who took hepatotoxic overdoses of acetaminophen in the second or third trimester (Rosevear & Hope, 1989; Thornton & Minns, 2012; Franko et al., 2013).
LONG-TERM HEALTH OUTCOMES
There is controversy over whether the limited positive associations that have been observed between maternal use of acetaminophen during pregnancy and asthma in the child reflect a causal relationship or result from incompletely controlled confounding due to maternal asthma or infections (Migliore et al., 2015).
Acetaminophen use during pregnancy has been associated with an increased risk of asthma/wheeze in children whose mothers used acetaminophen during pregnancy in multiple prospective and retrospective cohort studies (Sordillo et al., 2015; Liu et al., 2016; Magnus et al., 2016; Shaheen et al., 2019; Liew et al., 2021) but this association is not found in all investigations (Piler et al., 2018).
An elevated risk of childhood asthma was associated with gestational acetaminophen exposure in a meta-analysis that included 1,043,109 individuals (odds ratio=1.19, 95% confidence interval 1.12-1.27; p<0.00001) (Fan et al., 2017). This relationship remained significant when the sample was restricted to children with first trimester acetaminophen exposure only (odds ratio=1.21, 95% confidence interval 1.14-1.28). A 2021 analysis of six systematic reviews and three additional studies reported a maximum of a 1.5-fold increase in odds of asthma developing in acetaminophen exposed children (Singh et al., 2021).
In a record-linkage study from Taiwan, an increased prevalence of maternal acetaminophen use in pregnancy was reported among 2529 mothers of children affected with atopic dermatitis compared to mothers of unaffected children (Li et al., 2021). The associations were dose-dependent and strongest when acetaminophen exposure occurred in the first or second trimester or in all trimesters of pregnancy.
A growing number of studies and reviews have raised considerable public attention reporting associations of prenatal acetaminophen use and adverse childhood neurodevelopmental outcomes (Bauer et al., 2021). However, some investigators cautioned against an inference of causality based on inadequate evidence from the reported data (Liew & Ernst, 2021; Alwan et al., 2022; Damkier et al., 2022). It is important to note that the studies reported below suffer from serious biases, including variability in selection and adjustment of various potential confounders as well as issues with quality and validity of neurodevelopmental outcome definitions.
An increased risk of attention-deficit/hyperactivity disorder in children whose mothers used acetaminophen during pregnancy has been reported in numerous epidemiology studies (Liew et al., 2014; Thompson et al., 2014; Ystrom et al., 2017; Chen et al., 2019; Baker et al., 2020) and a 2019 meta-analysis of 244,940 mother-child dyads (pooled adjusted risk ratio=1.25, 95% confidence interval 1.17-1.34) (Gou et al., 2019). Third trimester exposure appeared to be related to a higher prevalence of attention-deficit/hyperactivity disorder childhood diagnoses. Several cohort studies have also reported associations of maternal acetaminophen use during pregnancy and increased odds of having a child on the autism spectrum (Avella-Garcia et al., 2016; Liew et al., 2016b; Ji et al., 2020). A meta-analysis of data from 132,738 mother-child pairs identified a modest increase for autism spectrum diagnoses in children born to mothers who used acetaminophen during pregnancy (risk ratio=1.19, 95% confidence interval 1.14-1.25) (Masarwa et al., 2018). The authors noted that this finding was likely influenced by uncontrolled confounding variables. Furthermore, a broad range of other cognitive and behavioral outcomes including conduct problems, reduced IQ scores, deficits in executive function, and oppositional defiant disorder symptoms have been associated with maternal use of acetaminophen during pregnancy (Liew et al., 2016a, c; Stergiakouli et al., 2016; Ruisch et al., 2018; Golding et al., 2020; Rifas-Shiman et al., 2020; Tronnes et al., 2020; Inoue et al., 2021). Delays in early communication and language development have also been documented in children prenatally exposed to acetaminophen (Vlenterie et al., 2016; Bornehag et al., 2018).
In contrast, results from several large population-based cohort studies demonstrated either no effect of acetaminophen on cognitive/behavioral performance or inconclusive results (Brandlistuen et al., 2013; Laue et al., 2019; Bertoldi et al., 2020; Tovo-Rodrigues et al., 2020).
OTHER NEURODEVELOPMENTAL OUTCOMES
An increased risk of cerebral palsy was found among children born to 90,952 mothers who used acetaminophen during pregnancy in the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study, but the association was of borderline statistical significance (adjusted odds ratio=1.3, 95% confidence interval 1.0-1.7) (Petersen et al., 2018).
ANIMAL TERATOLOGY STUDIES
Studies in pregnant mice and rats have shown no evidence of a teratogenic effect of acetaminophen treatment in doses similar to those used clinically in humans (Scialli et al., 2010). Similarly, mouse studies using human therapeutic levels of treatment found no adverse effect of maternal acetaminophen treatment on litter size (Iacob et al., 2019), offspring hyperkinetic behavior (Saad et al., 2016), and risk of allergic airway disease (Lee et al., 2015). In two independent studies however, reduced fetal weights and increased airway inflammation were observed in animals with a history of prenatal exposure (Karimi et al., 2015; Thiele et al., 2015). Alterations of several behavioral endpoints were observed among the offspring of pregnant rats treated with acetaminophen at a dose falling within the human therapeutic range, in an experimental study that suggests acetaminophen may be a developmental neurotoxicant (Klein et al., 2020).
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)
Abe K, Honein MA, Moore CA: Maternal febrile illnesses, medication use, and the risk of congenital renal anomalies. Birth Defects Res Part A Clin Mol Teratol 67(11):911-918, 2003. [E]
Allegaert K, Mian P, Lapillonne A, van den Anker JN: Maternal paracetamol intake and fetal ductus arteriosus constriction or closure: a case series analysis. Br J Clin Pharmacol 85(1):245-251, 2019. [S]
Alwan S, Conover EA, Harris-Sagaribay L, Lamm SH, Lavigne SV, Lusskin SI, Obican SG, Romeo AN, Scialli AR, Wisner KL: Paracetamol use in pregnancy--caution over causal inference from available data. Nat Rev Endocrinol 18(3):190, 2022. [O]
Aselton PA, Jick H, Milunsky A, Hunter JR, Stergachis A: First-trimester drug use and congenital disorders. Obstet Gynecol 65(4):451-455, 1985. [E]
Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, Garcia-Esteban R, Galan IR, Tardon A, Rodríguez-Bernal CL, Iniguez C, Andiarena A, Santa-Marina L, Sunyer J: Acetaminophen use in pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol 45(6):1987-1996, 2016. [E]
Aw MM, Dhawan A, Baker AJ, Mieli-Vergani G: Neonatal paracetamol poisoning. Arch Dis Child Fetal Neonatal Ed 81(1):F78, 1999. [C]
Baker BH, Lugo-Candelas C, Wu H, Laue HE, Boivin A, Gillet V, Aw N, Rahman T, Lepage JF, Whittingstall K, Bellenger J-P, Posner J, Takser L, Baccarelli AA: Association of prenatal acetaminophen exposure measured in meconium with risk of attention-deficit/hyperactivity disorder mediated by frontoparietal network brain connectivity. JAMA Pediatr 174(11):1073-1081, 2020. [E]
Bauer AZ, Swan SH, Kriebel D, Liew Z, Taylor HS, Bornehag C-G, Andrade AM, Olsen J, Jensen RH, Mitchell RT, Skakkebaek NE, Jegou B, Kristensen DM: Paracetamol use during pregnancy--a call for precautionary action. Nat Rev Endocrinol 17(12):757-766, 2021. [R]
Bertoldi AD, Rifas-Shiman SL, Boing AC, da Silva Dal Pizzol T, Miranda VIA, Silveira MPT, Freitas Silveira M, Domingues MR, Santos IS, Bassani DG, Tovo-Rodrigues L, Oken E: Associations of acetaminophen use during pregnancy and the first year of life with neurodevelopment in early childhood. Paediatr Perinat Epidemiol 34(3):267-277, 2020. [E]
Bornehag C-G, Reichenberg A, Hallerback MU, Wikstrom S, Koch HM, Jonsson BA, Swan SH: Prenatal exposure to acetaminophen and children's language development at 30 months. Eur Psychiatry 51:98-103, 2018. [E]
Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H: Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 42(6):1702-1713, 2013. [E]
Castro CT, Gama RS, Pereira M, Oliveira MG, Dal-Pizzol TS, Barreto ML, Santos DB: Effect of acetaminophen use during pregnancy on adverse pregnancy outcomes: a systematic review and meta-analysis. Expert Opin Drug Saf 21(2):241-251, 2022. [R]
Chen M-H, Pan T-L, Wang P-W, Hsu J-W, Huang K-L, Su T-P, Li C-T, Lin W-C, Tsai S-J, Chen T-J, Bai Y-M: Prenatal exposure to acetaminophen and the risk of attention-deficit/hyperactivity disorder: a nationwide study in Taiwan. J Clin Psychiatry 80(5):18m12612, 2019. [E]
Cleves MA, Savell VH Jr, Raj S, Zhao W, Correa A, Werler MM, Hobbs CA: Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects. Birth Defects Res Part A Clin Mol Teratol 70(3):107-113, 2004. [E]
Damkier P, Cleary B, Weber-Schoendorfer C, Shechtman S, Cassina M, Panchaud A, Diav-Cirtin O: Handle with care--interpretation, synthesis and dissemination of data on paracetamol in pregnancy. Nat Rev Endocrinol 18(3):191, 2022. [O]
Dathe K, Frank J, Padberg S, Hultzsch S, Meixner K, Beck E, Meister R, Schaefer C: Negligible risk of prenatal ductus arteriosus closure or fetal renal impairment after third-trimester paracetamol use: evaluation of the German Embryotox cohort. BJOG 126(13):1560-1567, 2019. [E]
Fan G, Wang B, Liu C, Li D: Prenatal paracetamol use and asthma in childhood: a systematic review and meta-analysis. Allergol Immunopathol 45(6):528-533, 2017. [R]
Feldkamp ML, Meyer RE, Krikov S, Botto LD: Acetaminophen use in pregnancy and risk of birth defects: findings from the National Birth Defects Prevention Study. Obstet Gynecol 115(1):109-115, 2010. [E]
Franko KR, Mekeel KL, Woelkers D, Khanna A, Hemming AW: Accidental acetaminophen overdose results in liver transplant during second trimester of pregnancy: a case report. Transplant Proc 45(5):2063-2065, 2013. [C]
Golding J, Gregory S, Clark R, Ellis G, Iles-Caven Y, Northstone K: Associations between paracetamol (acetaminophen) intake between 18 and 32 weeks gestation and neurocognitive outcomes in the child: a longitudinal cohort study. Paediatr Perinat Epidemiol 34(3):257-266, 2020. [E]
Gou X, Wang Y, Tang Y, Qu Y, Tang J, Shi J, Xiao D, Mu D: Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: a meta-analysis. Aust N Z J Psychiatry 53(3):195-206, 2019. [R]
Iacob RE, Iacob D, Moleriu RD, Tit DM, Bungau S, Otrisal P, Aleya S, Judea-Pusta C, Cioca G, Bratu OG, Aleya L, Petre I: Consequences of analgesics use in early pregnancy: results of tests on mice. Sci Total Environ 691:1059-1064, 2019. [A]
Inoue K, Ritz B, Ernst A, Tseng WL, Yuan Y, Meng Q, Ramlau-Hansen CH, Strandberg-Larsen K, Arah OA, Obel C, Li J, Olsen J, Liew Z: Behavioral problems at age 11 years after prenatal and postnatal exposure to acetaminophen: parent-reported and self-reported outcomes. Am J Epidemiol 190(6):1009-1020, 2021. [E]
Jensen MS, Henriksen TB, Rebordosa C, Thulstrup AM, Toft G, Sorensen HT, Bonde JP, Olsen J: Analgesics during pregnancy and cryptorchidism: additional analyses. Epidemiology 22(4):610-612, 2011. [E]
Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sorensen HT, Bonde JP, Henriksen TB, Olsen J: Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology 21(6):779-785, 2010. [E]
Ji Y, Azuine RE, Zhang Y, Hou W, Hong X, Wang G, Riley A, Pearson C, Zuckerman B, Wang X: Association of cord plasma biomarkers of in utero acetaminophen exposure with risk of attention-deficit/hyperactivity disorder and autism spectrum disorder in childhood. JAMA Psychiatry 77(2):180-189, 2020. [E]
Jick H, Holmes LB, Hunter JR, Madsen S, Stergachis A: First-trimester drug use and congenital disorders. JAMA 246(4):343-346, 1981. [E]
Karimi K, Kessler T, Thiele K, Ramisch K, Erhardt A, Huebener P, Barikbin R, Arck P, Tiegs G: Prenatal acetaminophen induces liver toxicity in dams, reduces fetal liver stem cells, and increases airway inflammation in adult offspring. J Hepatol 62(5):1085-1091, 2015. [A]
Kerr SM, Van Bennekom CM, Mitchell AA: Risk factors for congenital microcephaly in the pre-Zika era. Birth Defects Res 111(2):96-118, 2019. [E]
Killion JA, Chambers C, Smith CJF, Bandoli G: Prenatal acetaminophen use in women with autoimmune disorders and adverse pregnancy and birth outcomes. Rheumatology 2021 Aug 3 (published online ahead of print). [E]
Klein RM, Rigobello C, Vidigal CB, Moura KF, Barbosa DS, Gerardin DCC, Ceravolo GS, Moreira EG: Gestational exposure to paracetamol in rats induces neurofunctional alterations in the progeny. Neurotoxicol Teratol 77:106838, 2020. [A]
Kristensen DM, Hass U, Lesne L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jegou B, Leffers H: Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod 26(1):235-244, 2011. [E] & [A]
Laue HE, Cassoulet R, Abdelouahab N, Serme-Gbedo YK, Desautels A-S, Brennan KJM, Bellenger J-P, Burris HH, Coull BA, Weisskopf MG, Takser L, Baccarelli AA: Association between meconium acetaminophen and childhood neurocognitive development in GESTE, a Canadian cohort study. Toxicol Sci 167(1):138-144, 2019. [E]
Lee DCP, Walker SA, Byrne AJ, Gregory LG, Buckley J, Bush A, Shaheen SO, Saglani S, Lloyd CM: Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life. Thorax 70(6):528-536, 2015. [A]
Li C-Y, Dai Y-X, Chang Y-T, Bai Y-M, Tsai S-J, Chen T-J, Chen M-H: Prenatal exposure to acetaminophen increases the risk of atopic dermatitis in children: a nationwide nested case-control study in Taiwan. Pediatr Allergy Immunol 32(5):1080-1088, 2021. [E]
Li D-K, Liu L, Odouli R: Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 327(7411):368, 2003. [E]
Liew Z, Bach CC, Asarnow RF, Ritz B, Olsen J: Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years. Int J Epidemiol 45(6):2009-2017, 2016a. [E]
Liew Z, Ernst A: Intrauterine exposure to acetaminophen and adverse developmental outcomes: epidemiological findings and methodological issues. Curr Environ Health Rep 8(1):23-33, 2021. [R]
Liew Z, Ritz B, Rebordosa C, Lee P-C, Olsen J: Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 168(4):313-320, 2014. [E]
Liew Z, Ritz B, Virk J, Arah OA, Olsen J: Prenatal use of acetaminophen and child IQ: a Danish Cohort study. Epidemiology 27(6):912-918, 2016c. [E]
Liew Z, Ritz B, Virk J, Olsen J: Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in childhood: A Danish national birth cohort study. Autism Res 9(9):951-958, 2016b. [E]
Liu X, Liew Z, Olsen J, Pedersen LH, Bech BH, Agerbo E, Yuan W, Li J: Association of prenatal exposure to acetaminophen and coffee with childhood asthma. Pharmacoepidemiol Drug Saf 25(2):188-195, 2016. [E]
Liew Z, Yuan Y, Meng Q, von Ehrenstein OS, Cui X, Flores MES, Ritz B: Prenatal exposure to acetaminophen and childhood asthmatic symptoms in a population-based cohort in Los Angeles, California. Int J Environ Res Public Health 18(19):10107, 2021. [E]
Magnus MC, Karlstad O, Haberg SE, Nafstad P, Davey Smith G, Nystad W: Prenatal and infant paracetamol exposure and development of asthma: the Norwegian Mother and Child Cohort Study. Int J Epidemiol 45(2):512-522, 2016. [E]
Marsh CA, Cragan JD, Alverson CJ, Correa A: Case-control analysis of maternal prenatal analgesic use and cardiovascular malformations: Baltimore-Washington Infant Study. Am J Obstet Gynecol 211(4):404.e1-404.e9, 2014. [E]
Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I: Prenatal exposure to acetaminophen and risk for attention deficit hyperactivity disorder and autistic spectrum disorder: a systematic review, meta-analysis, and meta-regression analysis of cohort studies. Am J Epidemiol 187(8):1817-1827, 2018. [R]
Migliore E, Zugna D, Galassi C, Merletti F, Gagliardi L, Rasero L, Trevisan M, Rusconi F, Richiardi L: Prenatal paracetamol exposure and wheezing in childhood: causation or confounding? PLoS One 10(8):e0135775, 2015. [E]
Pastore LM, Hertz-Picciotto I, Beaumont JJ: Risk of stillbirth from medications, illnesses and medical procedures. Paediatr Perinat Epidemiol 13(4):421-430, 1999. [E]
Petersen TG, Liew Z, Andersen AN, Andersen GL, Andersen PK, Martinussen T, Olsen J, Rebordosa C, Tollanes MC, Uldall P, Wilcox AJ, Strandberg-Larsen K: Use of paracetamol, ibuprofen or aspirin in pregnancy and risk of cerebral palsy in the child. Int J Epidemiol 47(1):121-130, 2018. [E]
Piler P, Svancara J, Kukla L, Pikhart H: Role of combined prenatal and postnatal paracetamol exposure on asthma development: the Czech ELSPAC study. J Epidemiol Community Health 72(4):349-355, 2018. [E]
Puho EH, Szunyogh M, Metneki J, Czeizel AE: Drug treatment during pregnancy and isolated orofacial clefts in Hungary. Cleft Palate Craniofac J 44(2):194-202, 2007. [E]
Rebordosa C, Kogevinas M, Bech BH, Sorensen HT, Olsen J: Use of acetaminophen during pregnancy and risk of adverse pregnancy outcomes. Int J Epidemiol 38(3):706-714, 2009. [E]
Rebordosa C, Kogevinas M, Horvath-Puho E, Norgard B, Morales M, Czeizel AE, Vilstrup H, Sorensen HT, Olsen J: Acetaminophen use during pregnancy: effects on risk for congenital abnormalities. Am J Obstet Gynecol 198(2):178.e1-178.e7, 2008. [E]
Rifas-Shiman SL, Cardenas A, Hivert MF, Tiemeier H, Bertoldi AD, Oken E: Associations of prenatal or infant exposure to acetaminophen or ibuprofen with mid-childhood executive function and behaviour. Paediatr Perinat Epidemiol 34(3):287-298, 2020. [E]
Rosa F: Personal Communication, 1993. Cited in: Briggs GG, Freeman RK, Towers CV, Forinash AB. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 11th ed. Philadelphia, Pa.: Wolters Kluwer, 2017, p 10. [E]
Rosevear SK, Hope PL: Favourable neonatal outcome following maternal paracetamol overdose and severe fetal distress. Case report. Br J Obstet Gynaecol 96(4):491-493, 1989. [C]
Ruisch IH, Buitelaar JK, Glennon JC, Hoekstra PJ, Dietrich A: Pregnancy risk factors in relation to oppositional-defiant and conduct disorder symptoms in the Avon Longitudinal Study of Parents and Children. J Psychiatr Res 101:63-71, 2018. [E]
Saad A, Hegde S, Kechichian T, Gamble P, Rahman M, Stutz SJ, Anastasio NC, Alshehri W, Lei J, Mori S, Kajs B, Cunningham KA, Saade G, Burd I, Costantine M: Is there a causal relation between maternal acetaminophen administration and ADHD? PLoS One 11(6):e0157380, 2016. [A]
Scialli AR, Ang R, Breitmeyer J, Royal MA: A review of the literature on the effects of acetaminophen on pregnancy outcome. Reprod Toxicol 30(4):495-507, 2010. [R]
Shaheen SO, Lundholm C, Brew BK, Almqvist C: Prescribed analgesics in pregnancy and risk of childhood asthma. Eur Respir J 53(5):1801090, 2019. [E]
Shaw GM, Todoroff K, Velie EM, Lammer EJ: Maternal illness, including fever, and medication use as risk factors for neural tube defects. Teratology 57(1):1-7, 1998. [E]
Singh M, Varukolu S, Chauhan A, Jaiswal N, Pradhan P, Mathew JL, Singh M: Paracetamol exposure and asthma: what does the evidence say? An overview of systematic reviews. Pediatr Pulmonol 56(10):3189-3199, 2021. [R]
Smarr MM, Bible J, Gerlanc N, Buck Louis GM, Bever A, Grantz KL: Comparison of fetal growth by maternal prenatal acetaminophen use. Pediatr Res 86(2):261-268, 2019. [E]
Snijder CA, Kortenkamp A, Steegers EAP, Jaddoe VWV, Hofman A, Hass U, Burdorf A: Intrauterine exposure to mild analgesics during pregnancy and the occurrence of cryptorchidism and hypospadia in the offspring: the Generation R Study. Hum Reprod 27(4):1191-1201, 2012. [E]
Sordillo JE, Scirica CV, Rifas-Shiman SL, Gillman MW, Bunyavanich S, Camargo CA Jr, Weiss ST, Gold DR, Litonjua AA: Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children. J Allergy Clin Immunol 135(2):441-448, 2015. [E]
Stergiakouli E, Thapar A, Davey Smith G: Association of acetaminophen use during pregnancy with behavioral problems in childhood: evidence against confounding. JAMA Pediatr 170(10):964-970, 2016. [E]
Thiele K, Solano ME, Huber S, Flavell RA, Kessler T, Barikbin R, Jung R, Karimi K, Tiegs G, Arck PC: Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice. Am J Pathol 185(10):2805-2818, 2015. [A]
Thompson JMD, Waldie KE, Wall CR, Murphy R, Mitchell EA; ABC study group: Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years. PLoS One 9(9):e108210, 2014. [E]
Thornton SL, Minns AB: Unintentional chronic acetaminophen poisoning during pregnancy resulting in liver transplantation. J Med Toxicol 8(2):176-178, 2012. [C]
Thulstrup AN, Sorensen HT, Nielsen GL, Andersen L, Barrett D, Vilstrup H, Olsen J: Fetal growth and adverse birth outcomes in women receiving prescriptions for acetaminophen during pregnancy. Am J Perinatol 16(7):321-326, 1999. [E]
Tovo-Rodrigues L, Carpena MX, Martins-Silva T, Santos IS, Anselmi L, Barros AJD, Barros FC, Bertoldi AD, Matijasevich A: Low neurodevelopmental performance and behavioural/emotional problems at 24 and 48 months in Brazilian children exposed to acetaminophen during foetal development. Paediatr Perinat Epidemiol 34(3):278-286, 2020. [E]
Tronnes JN, Wood M, Lupattelli A, Ystrom E, Nordeng H: Prenatal paracetamol exposure and neurodevelopmental outcomes in preschool-aged children. Paediatr Perinat Epidemiol 34(3):247-256, 2020. [E]
Vlenterie R, Wood ME, Brandlistuen RE, Roeleveld N, van Gelder MM, Nordeng H: Neurodevelopmental problems at 18 months among children exposed to paracetamol in utero: a propensity score matched cohort study. Int J Epidemiol 45(6):1998-2008, 2016. [E]
Weber KA, Yang W, Carmichael SL, Padula AM, Shaw GM: A machine learning approach to investigate potential risk factors for gastroschisis in California. Birth Defects Res. 2019 Mar 1;111(4):212-221, 2019. [E]
Werler MM, Louik C, Mitchell AA: Epidemiologic analysis of maternal factors and amniotic band defects. Birth Defects Res Part A Clin Mol Teratol 67(1):68-72, 2003. [E]
Werler MM, Sheehan JE, Mitchell AA: Maternal medication use and risks of gastroschisis and small intestinal atresia. Am J Epidemiol 155(1):26-31, 2002. [E]
Wilkes JM, Clark LE, Herrera JL: Acetaminophen overdose in pregnancy. South Med J 98(11):1118-1122, 2005. [R]
Ystrom E, Gustavson K, Brandlistuen RE, Knudsen GP, Magnus P, Susser E, Davey Smith G, Stoltenberg C, Suren P, Haberg SE, Hornig M, Lipkin WI, Nordeng H, Reichborn-Kjennerud T: Prenatal exposure to acetaminophen and risk of ADHD. Pediatrics 140(5):e20163840, 2017. [E]
Zierler S, Rothman KJ: Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy. N Engl J Med 313(6):347-352, 1985. [E]